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Helping Immune Cells Fight Cancer

Cancer cells
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Our understanding of cancer, in particular, solid tumors, has improved tremendously. Since the synthesis of monoclonal antibodies in 1975, we have developed a plethora of immune checkpoint inhibitors using monoclonal antibodies (mAbs) for cancer treatment. However, mAbs have poor biodistribution in the body and do not work when there is mutational escape by cancer cells, necessitating a more advanced form of cancer immunotherapy.

In 1988, Dr. Steven Rosenberg used tumor-infiltrating lymphocytes (TILs) to treat melanoma. A year later, the first generation of Chimeric Antigen Receptor T (CAR T) cell was constructed.

There are now six US Food and Drug Administration (FDA)-approved CAR T-cell products in the market for cancer treatment, and as of January 2024, more than 950 registered clinical trials on ClinicalTrials.gov; the majority (93%) focusing on autologous CART-cell products.

Despite the promise of TIL and CAR-T cell therapy, major challenges exist in using them to treat solid tumors, due to poor infiltration of immune cells into solid tumors. Here, immune cells would refer to clinically beneficial immune cell types including CD4+ helper and CD8+ cytotoxic T cells. Even after immune cells are able to infiltrate into solid tumors, the harsh tumor microenvironment, including low glucose levels, hypoxia and low pH, suppresses the functions of therapeutic immune cells. Here, we will try to understand how these obstacles reduce the efficacy of cell-based cancer immunotherapy and strategies to overcome them.

Overcoming the extracellular matrix

The immune landscape in solid tumors can be broadly classified into inflamed, immune excluded and immune desert, based on spatial distribution of CD8+ T cells in the tumor microenvironment.

An example of an immune desert or immune excluded cancer is pancreatic ductal adenocarcinoma (PDAC). Immune desert refers to a state where CD8+ T cells are absent from the tumor and its periphery, whereas immune excluded refers to a state where there are CD8+ T cells accumulation but insufficient infiltration into tumors. One of the major factors causing this is the thick extracellular matrix surrounding solid tumors. The matrix is composed of proteins such as collagen secreted by cancer-associated fibroblasts (CAFs).

McAndrews at el. found that there is significant heterogeneity of CAFs in PDAC. Fibroblast activation protein (FAP)+ CAFs were found to be tumor promoting, and their depletion enhanced survival in mouse PDAC model. On the other hand, alpha smooth muscle actin (αSMA)+ CAFs were found to be tumor restraining. This recent finding suggests that inhibition of FAP+ CAFs is a useful therapeutic target to reduce collagen secretion and extracellular matrix barrier to enhance CD8+ T cell infiltration into solid tumors.

Altering metabolic states of the tumor microenvironment

Even when CD8+ T cells are able to infiltrate into solid tumors, their biological activities can be suppressed due to poor availability of nutrients, low pH and oxygen levels.

Immunometabolism cancer therapy, is emerging as a promising paradigm to regulate immune cell fates and potentiates their anti-tumor immunity. It disrupts cancer metabolic signaling pathways such as glycolysis, tricarboxylic acid cycle and amino acid metabolism to reverse the immunosuppressive tumor microenvironment.

Adenosine metabolism, in particular, has been found to play an important role in facilitating tumor immune surveillance escape, and promoting cancer progression and metastasis via restraining immune effector cell infiltration and cytotoxicity. It is known that tumors coopt the CD73/adenosine system as a mechanism for promoting tumor growth and progression, angiogenesis and immune escape.

Some strategies to manipulate adenosine metabolism include encapsulating pharmacological inhibitors, monoclonal antibodies, siRNA and even CRISPR/cas9 to inhibit or shut down the activities of CD73.

Importantly, as adenosine metabolism can also occur via CD73-independent pathways, it will be more beneficial to therapeutically combine CD73 inhibition with other adenosine-associated metabolic pathways to comprehensively disrupt the adenosinergic axis in cancer metabolism.

The road ahead

A recent announcement by the FDA, mandating CART-cell manufacturers to add a general boxed warning of potential T cell malignancies, has caused a temporary shock to the CAR T field. In an earlier statement published in November 2023, the FDA said that “although the overall benefits of these products continue to outweigh their potential risks for their approved uses, FDA is investigating the identified risk of T cell malignancy with serious outcomes, including hospitalization and death, and is evaluating the need for regulatory action.” A comment piece, published in Nature Medicine by Levine et al., stated that existing data suggests that CART-cell therapy has a low risk of secondary malignancies compared to other cancer treatments.

The use of immune cells for cancer therapy is showing no signs of slowing down. Besides CD4+ and CD8+ T cells, other immune cell types including macrophages and natural killer cells are being engineered with CAR constructs for cancer treatment. Each of these cell types have their distinct advantages and may be arguably suited for different cancer types. For instance, the use of CAR macrophages, which are highly prevalent in tumors, to treat cancers that are classified as immune desert.

Taking a step back, besides T cell infiltration and metabolism, innovations are also necessary to manufacture T cells that proliferate fast while maintaining their critical biological attributes to reduce costs and delays, and to deliver immune cell therapies to cancer patients who need them the most.